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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1775.)
© 2003 American Heart Association, Inc.

Vascular Biology

Inhibition of Tumor Necrosis Factor-–Induced SHP-2 Phosphatase Activity by Shear Stress

A Mechanism to Reduce Endothelial Inflammation

Nicole Lerner-Marmarosh^*; Masanori Yoshizumi^*; Wenyi Che^*; James Surapisitchat; Hisaaki Kawakatsu; Masashi Akaike; Bo Ding; Qunhua Huang; Chen Yan^*; Bradford C. Berk; Jun-ichi Abe

From the Center for Cardiovascular Research, University of Rochester, NY, and the Lung Biology Center (H.K.), University of California, San Francisco, Calif.

Correspondence to Jun-ichi Abe, MD, PhD, Cardiology Unit, Box 679, 601 Elmwood Ave, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642. E-mail jun-ichi_abe{at}urmc.rochester.edu

Objectives— Atherosclerosis preferentially occurs in areas of turbulent flow, whereas laminar flow is atheroprotective. Inflammatory cytokines have been shown to stimulate adhesion molecule expression in endothelial cells that may promote atherosclerosis, in part, by stimulating c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-B transcriptional activity.

Methods and Results— Because Src kinase family and Src homology region 2-domain phosphatase-2 (SHP-2) may regulate JNK activation, we studied the effect of shear stress on endothelial inflammation and JNK. Human umbilical vein endothelial cells preexposed to flow showed decreased tumor necrosis factor (TNF)-–induced c-Jun and NF-B transcriptional activation. TNF-–mediated JNK, c-Jun, and NF-B activation required Src and SHP-2 activity. Shear stress significantly inhibited SHP-2 phosphatase activity without affecting TNF-–induced Src family kinase activation. Because MEKK3 and Gab1 are critical for TNF-–induced c-Jun and NF-B activation, we determined the role of SHP-2 phosphatase activity in MEKK3 signaling. A catalytically inactive form of SHP-2 increased MEKK3/Gab1 interaction and inhibited MEKK3 (but not MEKK1)-mediated c-Jun and NF-B activation.

Conclusions— These results suggest that SHP-2 is a key mediator for the inhibitory effects of shear stress on TNF- signaling in part via regulating MEKK3/Gab1 interaction, MEKK3 signaling, and subsequent adhesion molecule expression.

Key Words: pathophysiology • cell signaling • endothelium • mechanism of atherosclerosis

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